Azepanes

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is phenyl or alpha- or beta-naphthyl, which groups can be substituted by hydroxy, lower-alkyl, lower-alkoxy, lower alkoxy-carbonyl, phenoxy, acyloxy, hydroxyphenoxy-sulfonyl, halogen, nitro, amino, acylamino or N-lower-alkyl-acylamino; 
     R 2  is phenyl or phenyl substituted by hydroxy or acyloxy; 
     Y is a carbon-carbon bond or is vinylene; and 
     n is 1,2 or 3; 
     and pharmaceutically acceptable acid addition salts thereof are protein kinase inhibitors and can be used for the treatment of disorders mediated by such enzymes, for example, inflammatory diseases.

This application is a continuation of U.S. application Ser. No.08/831,269 filed Mar. 31, 1997, now U.S. Pat. No. 5,907,038 which is acontinuation of U.S. application Ser. No. 08/661,276 filed Jun. 10,1996, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to azepanes which inhibit protein kinases.

2. Summary of the Invention

The present invention relates to azepanes and their ring homologs of theformula ##STR2## wherein R¹ is phenyl or alpha- or beta-naphthyl, whichgroups can be substituted by hydroxy, lower-alkyl, lower-alkoxy, loweralkoxy-carbonyl, phenoxy, acyloxy, hydroxyphenoxy-sulfonyl, halogen,nitro, amino, acylamino or N-lower-alkyl-acylamino;

R² is phenyl or phenyl substituted by hydroxy or acyloxy;

Y is a carbon-carbon bond or is vinylene; and

n is 1,2 or 3;

and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I and their salts can be prepared in accordancewith the invention by cleaving off the protecting group Z and, ifnecessary, hydroxy and amino protecting groups present in R¹¹ and R²¹from a compound of the formula ##STR3## wherein Z is a protecting group,R¹¹ and R²¹ are R¹ and R², respectively, whereby the hydroxy and aminogroups contained in R¹ and R² can be present in protected form and R¹and R², Y and n are as defined above,

and, if desired, converting a compound of formula I obtained into apharmaceutically acceptable salt.

The invention is also concerned with the preparation of the compounds offormula I, pharmaceutical compositions containing a compound of formulaI or a pharmaceutically acceptable salt thereof in the manufacture ofpharmaceutical compositions for the therapy and prophylaxis ofconditions which are mediated by protein kinases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of the formula ##STR4##wherein R¹ is unsubstituted phenyl, alpha- or beta-naphthyl or phenyl oralpha- or beta-naphthyl substituted by hydroxy, lower-alkyl,lower-alkoxy, lower-alkoxy-carbonyl, phenoxy, acyloxy,hydroxyphenoxy-sulfonyl, halogen, nitro, amino, acylamino orN-lower-alkyl-acylamino;

R² is unsubstituted phenyl or phenyl substituted by hydroxy or acyloxy;

Y is a carbon-carbon bond or vinylene; and

n is 1, 2 or 3;

and pharmaceutically acceptable acid addition salts thereof.

The term "lower" used here denotes groups with 1-6, preferably 1-4, Catoms. Alkyl and alkoxy groups can be straight-chain or branched, suchas methyl, ethyl, propyl, isopropyl, n-butyl, sec.- and tert.-butyl,pentyl and hexyl and, respectively, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec. and tert.- butoxy, pentyloxy and hexyloxy.Acyl groups can be derived from aliphatic, araliphatic or aromaticcarboxylic acids, such as saturated and unsaturated aliphatic carboxylicacids, the hydrocarbon residues of which can be straight-chain orbranched, particularly lower alkanoic acids, or benzoic acid or benzoicacid substituted by one to three groups selected from hydroxy, loweralkoxy, halogen or nitro. Halogen denotes fluoro, chloro, bromo andiodo.

Preferably R¹ is phenyl substituted by phenyl, di-lower alkoxyphenyl,phenoxy, amino, hydroxy, lower alkoxy, lower alkoxy-carbonyl, nitro,halogen, hydroxy-substituted benzoylamino, hydroxy-substitutedbenzoyl-lower alkylamino, nitrobenzoyloxy and hydroxy-substitutedphenoxysulfonyl; and alpha- and beta-naphthyl; and hydroxy- and/or loweralkoxy substituted alpha- and beta-naphthyl.

Preferably R² is hydroxyphenyl, hydroxy-benzoyloxy-phenyl, di-loweralkyl-benzoyloxy-phenyl, and halogen-benzoyloxy-phenyl, n is preferably3.

A preferred group of compounds of formula I are those wherein Y is acarbon-carbon bond. Particularly preferred are compounds of formula Iwherein R¹ is hydroxyphenyl, benzoyloxyphenyl orp-nitrobenzoyloxyphenyl; R² is phenyl substituted by hydroxy- or hydroxyor halogen-substituted benzoyloxy.

The compounds of formula I and their salts can be prepared in accordancewith the invention by cleaving off the protecting group Z and, ifnecessary, hydroxy and amino protecting groups present in R¹¹ and R²¹from a compound of the formula ##STR5## wherein Y is a carbon-carbonbond or vinylene;

Z is a protecting group;

n is 1, 2 or 3;

R¹¹ is unsubstituted phenyl, alpha- or beta naphthyl or phenyl. alpha-or beta-naphthyl substituted by hydroxy, lower-alkyl, lower-alkoxy,loweralkoxy-carbonyl, phenoxy, acyloxy, hydroxyphenoxy-sulfonyl,halogen, nitro, amino, acylamino or N-lower-alkyl-acylamino whereby thehydroxy and amino groups present are unprotected or protected; and

R²¹ is phenyl or phenyl substituted by hydroxy or acyloxy whereby thehydroxy and amino groups present are unprotected or protected.

Examples of protecting groups Z and of amino protecting groups presentin the substituents R¹¹ and R²¹ are groups which are known for theprotection of amino groups, such as tert.-butoxycarbonyl. Methoxymethyl,benzyl and silyl ether groups such as tert.-butyl-dimethyl-silanyl areexamples of hydroxy protecting groups.

The cleavage of these protecting groups can be carried out in a knownmanner, such as by treatment with acids, for example, mineral acids,such as HCl, in an inert organic solvent, for example, an ether such asdimethoxyethane or an alcohol such as isopropanol or mixtures of suchsolvents, or by hydrogenolysis in the case of benzyl ether groups. Theacid cleavage of the protecting groups is conveniently effected at lowtemperatures, preferably at temperatures below room temperature,especially at about 0° C. Hydrogenolytic removal of a benzyl ether groupis conveniently carried out using a noble metal catalyst, such as Pd/Cat room temperature.

The compounds of formula I form salts in which they can be converted ina known manner. Examples of pharmaceutically acceptable salts of thecompounds of formula I are acid addition salts of mineral acids ororganic acids, such as hydrochloric acid or trifluoro acetic acid.

The compounds of formula II that are used to prepare the compounds offormula I are novel and also form part of the invention. They can beobtained as described in the Examples given below or in analogy thereto.

The compounds of formula I and their pharmaceutically usable salts areprotein kinase inhibitors; they inhibit cellular processes such as cellproliferation and cell secretion and can be used for the control orprevention of illnesses which are mediated by protein kinases, forexample, of inflammatory diseases, such as, arthritis. The compounds offormula I may also be useful in treating other disorders mediated byprotein kinase, such as immune diseases, psoriasis, contact dermatitis,in connection with organ transplants, as well as, in oncology. Theyinhibit cell infections with HIV (human immunodeficiency virus) orEpstein-Barr virus and are therefore suitable for the treatment of AIDSand infectious mononucleosis. Furthermore, the compounds in accordancewith the invention inhibit smooth muscle contraction and can thereforebe used in cardiovascular and bronchopulmonary illnesses. Further, theyare of value in asthma therapy. The compounds in accordance with theinvention also inhibit blood platelet aggragation and can be used forthe control or prevention of thromboses. Furthermore, they inhibit theliberation of mediators of activated neutrophils and can therefore beused in the control of ischemic damage, for example, in the heart orbrain. Further, they inhibit neurotoxicity caused by increased glucoselevel and are therefore of value in the treatment of diabeticcomplications. Finally, the compounds in accordance with the inventionstimulate hair growth and can therefore be used for the prevention orsuppression of hair loss.

Protein kinases play an important role as signal transmitters in manycell functions. In addition to tyrosine kinases, serine/threoninekinases such as protein kinase C (PKC) and cyclic AMP-dependent proteinkinase (PKA) are key enzymes in the signal transmission chain from thecell membrane to the cell nucleus.

The compounds in accordance with the invention inhibit serine/proteinkinases such as PKC and PKA not only as the isolated enzyme but also incells. They therefore inhibit important cell functions as mentionedabove, especially the activation and proliferation of T-lymphocytes andthe proliferation of keratinocytes.

Inhibitors of T-cell activation can be used as immunosuppressives foruse in illnesses such as rheumatoid arthritis, psoriasis and otherinflammatory skin disorders (atopic eczema, contact eczema), inautoimmune diseases, transplants and immunomediated alopecia.

Inhibitors of keratinocyte proliferation are of value for use in skindiseases having a hyperproliferative component in the epidermis,especially psoriasis. Inhibitors of cell proliferation can be used inoncology.

The aforementioned activities can be observed using the test proceduresdescribed hereinafter:

A: Inhibition of Protein Kinase C (PKC) (Isolated Enzyme)

Protein kinase C (PKC) activity is determined by measuring the transferof ³² P-labelled phosphate from ³² P-g-ATP (10 mM) to histone H1 (200mg/ml) as the substrate. Partially purified PKC from swine brain is usedas the enzyme source [DEAE chromatography according to the method of U.Kikkawa et al. (Methods Enzymol. 99, 288, 1983)]. Activation of the PKCis effected by phospholipid vesicle prepared by ultrasound treatment ofa mixture of 0.05 ml of phosphatidylserine (10 mg/ml) and 0.005 ml ofdiolein (10 mg/ml) in 5 ml of Tris-HCl buffer (20 mM, pH 7.4). The testsubstances are used in dimethyl sulphoxide (DMSO)/buffer in theconcentration range 0.001-100 mM. The test is started by the addition ofenzyme; after incubation at 32° C. for 2 minutes the reaction is stoppedby the addition of 20% trichloroacetic acid (with 1% SDS and 1% sodiumpyrophosphate). The precipitated radioactive histone protein isseparated from excess ATP by filtration over nitrocellulose membranesand the radioactivity on the filter is measured in a scintillationcounter. The inhibitory activity of the test substance is given as themicromolar concentration which is required to reduce the PKC activity by50% (IC₅₀ [mM]).

B: Inhibition of cAMP-Dependent Protein Kinase (PKA)

PKA activity is determined by measuring the transfer of ³² P-labelledphosphate from ³² P-g-ATP (10 mM) to histone H1 (333 mg/ml) as thesubstrate. Partially purified PKA from swine brain is used as the enzymesource [DEAE chromatography according to the method of U. Kikkawa et al.(Methods Enzymol. 99, 288, 1983)]. Activation of the PKA is effected bycyclic AMP (2 mM) in Tris-HCl buffer (20 mM, pH 7.4). The testsubstances are used in dimethyl sulfoxide (DMSO)/buffer in theconcentration range 0.001-100 mM. The test is started by the addition ofenzyme; after incubation at 32° C. for 2 minutes the reaction is stoppedby the addition of 20% trichloroacetic acid (with 1% SDS and 1% sodiumpyrophosphate). The precipitated radioactive histone protein isseparated from excess ATP by filtration over nitrocellulose membranesand the radioactivity on the filter is measured in a scintillationcounter. The inhibitory activity of the test substance is given as themicromolar concentration which is required to reduce the PKA activity by50% (IC₅₀ [mM]).

C: Cell Proliferation in Cultured Mouse Hair Follicles

Mouse whisker follicles were isolated and cultured according to themethod described by Buhl et al., J. Invest. Dermatol. 92, 315-320(1989). Whisker pads were removed from 4-day-old CD-1 mice and vibrissaewere carefully separated from the surrounding tissue with forceps undera dissecting microscope. Four hair follicles were incubated at 37° C. in2 cm² wells in 1 ml of M199 medium containing 20% fetal bovine serum. inthe presence or absence of test compound at varying concentrations. Eachtreatment group consisted of four wells. After 1 day of culture. ³H-thymidine was added to the wells to a final concentration of 5 μCi/mland the follicles were incubated for a further three days. The follicleswere then washed with phosphate-buffered saline and incorporatedradioactivity was solubilized by addition of 0.5 ml of 1.0M NaOH andincubation for 18 h at 37° C. An aliquot of the alkali extracted wastaken for measurement of radioactivity and results were expressed asdpm/follicle.

Calculation of Maximal Stimulation and ED₅₀ Values

The hair follicle ³ H-thymidine incorporation values (dpm/follicle),obtained as described above, were then expressed as a percentage ofcontrol levels as follows:

    % control DNA synthesis for test compound=((treatment dpm/follicle)/(control dpm/follicle))×100

The dose-response relationship for each compound was then used todetermine: 1) the maximal stimulation of DNA synthesis obtained for thatcompound, expressed as a percentage of control levels, and 2) the ED₅₀value, or the concentration (μM) of compound that gave rise to 50% ofthe maximal stimulation of DNA synthesis.

The results obtained with typical compounds of formula I in these testprocedures are compiled in the following Table I and II:

                  TABLE I                                                         ______________________________________                                                         Test Procedure*                                              Compound of Example                                                                              A       B                                                  ______________________________________                                        I/15               8.8     0.070                                                I/19 24 0.041                                                                 I/25 26 1.9                                                                   II/1 30 0.038                                                                 III/1 10 0.026                                                              ______________________________________                                         *the test data indicate the respective IC.sub.50 [mM                     

                  TABLE II                                                        ______________________________________                                                      Mouse Hair Follicle                                               DNA Synthesis                                                                               Maximal Stimulation                                                                         EC.sub.50                                         Compound of Example (% control) (μM)                                     ______________________________________                                        III/1           534 ± 52    5                                                II/1 468 ± 26 10                                                           I/19 371 ± 50 30                                                           I/28 349 ± 25 40                                                         ______________________________________                                    

The compounds of formula I and their salts can be used as medicaments,for example, in the form of pharmaceutical preparations.

The preparations can be administered enterally, parenterally ortopically. Preparations in the form of tablets, capsules, dragees,syrups, suspensions, solutions and suppositories are suitable forexample, for enteral administration. Preparations in the form ofinfusion or injection solutions are suitable for parenteraladministration.

The dosages in which the preparations are administered can varyaccording to the mode of use and route of use and on the requirements ofthe patient.

In the case of the oral administration of the compounds in accordancewith the invention, dosages of about 0.1-100 mg/kg, preferably 0.5-50mg/kg, per day come into consideration for adults.

The preparations can be administered in one or several dosages. Capsulescontaining about 5-500 mg of active ingredient represent a preferreddosage form.

The preparations can contain inert as well as pharmacodynamically activeadditives. Tablets or granulates, for example, can contain a series ofbinders, fillers, carrier substances or diluents. Liquid preparationscan be present, for example, in the form of a sterile water-misciblesolution. Capsules can contain, in addition to the active ingredient, afiller or thickener. Furthermore, flavor-improving additives as well assubstances usually used as preservatives, stabilizers, water-retainersand emulsifiers as well as salts for varying the osmostic pressure,buffers and other additives can also be present.

The previously mentioned carrier substances and diluents can be organicor inorganic substances, for example, water, gelatin, lactose, starch,magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.It is a prerequisite that all adjuvants used in the manufacture of thepreparations are non-toxic.

For topical use, the active ingredients are conveniently used in theform of ointments, tinctures, creams, solutions, lotions, sprays,suspensions and the like. Ointments and creams as well as solutions arepreferred. These preparations destined for topical use can bemanufactured by admixing the process products as active ingredients withnon-toxic, inert, solid or liquid carriers which are suitable fortopical treatment and which are conventional in such preparations.

For topical use there are suitable conveniently about 0.1-5%, preferably0.3-3%, solutions as well as about 0.1-5%, preferably about 0.3-2%,ointments and creams.

If desired, an antioxidant, for example, tocopherol,N-methyl-g-tocopheramine, as well as, t-butyl-hydroxyanisole ort-butyl-hydroxytoluene, can be admixed with the preparations.

The following Examples illustrate the invention further.

EXAMPLE I

1) 56 mg(3R,4R)-3-[4-(4-Fluoro-benzoyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester was dissolved in 2 ml dimethoxyethane and 2 mlisopropanol (i-Pr-OH); after cooling to 0° C. the solution was slowlysaturated with HCl-gas and stored in a refrigerator for 24 h. Thesolvent was completely removed in vacuo; the product was triturated withdiethylether; the resulting suspension was stirred for several hours.The solvent was decanted and stirring was continued overnight afteraddition of another portion of fresh solvent. The product was filtered,washed with several portions of diethylether and dried in vacuo (0.1mbar) at 50° C. 40 mg (85% yield) 4-Hydroxy-benzoic acid(3R,4R)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepan-4-yl esterhydrochloride (1:1) was obtained as a yellow powder

MS: m/e=493 (M+H)⁺

IR (KBr): 3415, 3269, 1741, 1703, 1641, 1605, 1541, 1507 cm⁻¹

In analogy there were obtained

2) Biphenyl-4-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1)from(3R,4R)-4-(Biphenyl-4-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 431 (M+H)⁺

IR: 3381, 3249, 2801, 2539, 1706, 1651, 1607, 1594, 1503 cm⁻¹

3) Naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1)from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(naphthalen-2-yl-2-carbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 405 (M+H)⁺

IR: 3402, 3265, 3062, 1707, 1854, 1630, 1607, 1535 cm⁻¹

4) Naphthalene-1-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1)from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(naphthalen-1-ylcarbonyloxy)-[4-(2-hydroxy-phenoxysulfonyl)-benzoyloxyl-azepane-1-carboxylicacid tert-butyl ester

MS: 404.9 (M+H)⁺

IR: 3392, 3241, 2801, 2544, 1713, 1635, 1608, 1540, 1506 cm⁻¹

5) 2-Phenoxy-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-ylester hydrochloride (1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(2-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 447 (M+H)⁺

IR: 3404, 3254, 2795, 2554, 1720, 1637, 1607, 1540, 1506, 1482 cm⁻¹

6) 4-Amino-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-ylester trifluoroacetate (1:1) from(3R,4R)-4-(4-tert-Butoxycarbonylamino-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 370 (M+H)⁺

IR: 3404, 2626, 1678, 1607, 1508, 1202, 1176, 845, 723 cm⁻¹

7) 3-Phenoxy-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-ylester trifluoroacetate (1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(3-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 447 (M+H)⁺

IR: 3387, 3167, 1722, 1677, 1634, 1607, 1583, 1544, 1509, 1486, 1441cm⁻¹

8) Biphenyl-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(Biphenyl-2-ylcarbonyloxy-2-carbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 431 (M+H)⁺

IR: 3375, 3061, 3027, 2602, 1676, 1638, 1608, 1543, 1507, 1449 cm⁻¹

9) 3-Methoxy-phthalic acid(3R,4R)-1-[3-(4-hydroxy-benzoylamino)-azepan-4-yl]ester 2-methyl estertrifluoroacetate (1:1) from 3-Methoxy-phthalic acid(3R,4R)-1-[1-tert-butoxycarbonyl-3-(4-hydroxy-benzoylamino)-azepan-4-yl]ester2-methyl ester

MS: 443 (M+H)⁺

IR: 3405, 3017, 2954, 2848, 1724, 1677, 1638, 1610, 1544 cm⁻¹

10) 3,5-Dimethoxy-naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(3,5-Dimethoxy-naphthalen-2-ylcarbonyloxy-)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 465 (M+H)⁺

IR: 3395, 3163, 2837, 1677, 1632, 1605, 1542, 1505, 1469 cm⁻¹

11) 3,7-Dimethoxy-naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(3,7-Dimethoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 465 (M+H)⁺

IR: 3394, 3065, 3009, 1780, 1677, 1636, 1607, 1543, 1507 cm⁻¹

12) 2,5-Dichloro-3-nitro-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1 from(3R,4R)-4-(2,5-Dichloro-3-nitro-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 468 (M+H)⁺

IR: 3419, 2608, 1738, 1676, 1637, 1607, 1545, 1507, 1440 cm⁻¹

13) 3-(4-Hydroxy-phenyl)-acrylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(E)-(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-[3-(4-hydroxy-phenyl)-acryloyloxy]-azepane-1-carboxylicacid tert-butyl ester

MS: 397 (M+H)⁺

IR: 3385, 2811, 1678, 1633, 1605, 1511, 1202, 1169, 980, 832, 722 cm⁻¹

14) 3',4'-Dimethoxy-biphenyl-4-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(3',4'-Dimethoxy-biphenyl-4-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 675 (M+H)⁺

IR: 3367, 3189, 3006, 2944, 2872, 1784, 1676, 1637, 1607, 1526, 1503cm⁻¹

15) 3,4-Dihydroxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(3,4-Dihydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 387 (M+H)⁺

IR: 3395, 2860, 1678, 1608, 1508, 1294, 1200, 1116, 847, 764, 721 cm⁻¹

16) 2,3-Dihydroxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(2,3-Dihydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 387 (M+H)⁺

IR: 3252, 2866, 1675, 1608, 1507, 1202, 1147, 846, 752, 722 cm⁻¹

17) 7-Hydroxy-3-methoxy-naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(7-hydroxy-3-methoxy-naphthalenne-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 451 (M+H)⁺

IR: 3386, 3059, 2969, 1785, 1677, 1636, 1608, 1543, 1507 cm⁻¹

18) 2,4-Dihydroxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(2,4-Dihydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 387 (M+H)⁺

IR: 3388, 2871, 1781, 1670, 1626, 1507, 1267, 1204, 1177, 1143, 874,848, 774, 699 cm⁻¹

19) 5-Hydroxy-3-methoxy-naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(5-hydroxy-3-methoxy-naphthalene-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 451 (M+H)⁺

IR: 3392, 3099. 1676, 1632, 1606, 1543, 1508, 1454 cm⁻¹

20) 3-Hydroxy-5-methoxy-naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(3-hydroxy-5-methoxy-naphthalene-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 451 (M+H)⁺

IR: 3384, 3288, 2598, 1779, 1680, 1635, 1607, 1542, 1511 cm⁻¹

21) 3-Hydroxy-7-methoxy-naphthalene-2-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(3-hydroxy-7-methoxy-naphthalene-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 451 (M+H)⁺

IR: 3411, 2615, 2594, 1679, 1636, 1608, 1542, 1510, 1470, 1440 cm⁻¹

22) 5-Fluoro-2-hydroxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-(5-Fluoro-2-hydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 389 (M+H)⁺

IR: 3282, 2852, 1679, 1633, 1607, 1486, 1201, 1070, 832, 784, 723 cm⁻¹

23) 4-Hydroxy-3,5-dimethoxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from (3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(4-hydroxy-3,5-dimethoxy-benzoylox)-azepane-1-carboxylicacid tert-butyl ester

MS: 431 (M+H)⁺

IR: 3393, 2968, 1678, 1609, 1510, 1338, 1279, 1207, 1181, 1114, 849,766, 722 cm⁻¹

24) 4-(2-Hydroxy-benzoylamino)-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-[4-(2-hydroxy-benzoylamino)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester

MS: 490 (M+H)⁺

IR: 3318, 3191, 3065, 2976, 2868, 2591, 1676, 1596, 1535, 1508 cm⁻¹

25) 4-[(2-Hydroxy-benzoyl)-methyl-amino]-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-{4-[(2-hydroxy-benzoyl)-methyl-amino]-benzoyloxy}-azepane-1-carboxylicacid tert-butyl ester

MS: 504 (M+H)⁺

IR: 3349, 3267, 2601, 1676, 1633, 1605, 1544, 1508, 1453 cm⁻¹

26) 4-[(2,6-Dihydroxy-benzoyl)-methyl-amino]-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-{4-[(2,6-Dihydroxy-benzoyl)-methyl-amino]-benzoyloxy}-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 520 (M+H)⁺

IR: 3392, 3118, 2874, 1676, 1605, 1544, 1508, 1467, 1439 cm⁻¹

27) 2-Hydroxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(2-hydroxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester

MS: 371 (M+H)⁺

IR: 3368, 2967, 1676, 1610, 1507, 1203, 1137, 847, 759, 722 cm⁻¹

28) 4-(2-Hydroxy-phenoxysulfonyl)-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1)from(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(naphthalene-1-carbonyloxy)-[4-(2-hydroxy-phenoxysulfonyl)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester

MS: 527.3 (M+H)⁺

IR: 3406, 2941, 1724, 1630, 1607, 1545, 1507, 1300, 1277, 1191, 1085,884, 810, 764 cm⁻¹

EXAMPLE II

1) Pd/C 10% was prehydrogenated in a mixture of methanol (5 ml) andtetrahydrofuran, then(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(2,6-bis-benzyloxy-benzoyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester was added. The reaction mixture was hydrogenatedat room temperature and atmospheric pressure until hydrogen uptakestopped. The catalyst was removed by filtration and the filtrate wasevaporated to dryness. The crude product was dissolved indichloromethane (8 ml), trifluoroacetic acid (4 ml) was added at 0° C.and the reaction mixture was stirred for 1 hour. After removal of thesolvent the residue was precipitated with diethylether, filtered anddried in high vacuo to yield 496 mg of pure 4-Hydroxy-benzoic acid(3R,4R)-3-[4-(2,6-dihydroxy-benzoyloxy)-benzoylamino]-azepan-4-yl estertrifluoroacetate (1:1) (yield 91.6%)

MS: 507 (M+H)⁺

IR: 3478, 3244, 3073, 1679, 1607, 1543, 1498 cm⁻¹

In analogy there was obtained

2) 4-(2,6-Dihydroxy-benzoylamino)-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester trifluoroacetate(1:1) from(3R,4R)-4-[4-(2,6-Bis-benzyloxy-benzoylamino)-benzoyloxy]-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

MS: 506.1 (M+H)⁺

IR: 3310, 3066, 2851, 1677, 1698, 1589, 1544, 1504, 1454 cm⁻¹

EXAMPLE III

1) 108.9 g(3R,4R)-3-[4-(Tetrahydro-pyran-2-yloxy)-benzoylamino]-4-[4-(tetrahydro-pyran-2-yloxy)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester (mixture of 4 diast.) was dissolved in 200 ml of a2N dimethoxyethane and i-Pr-OH (1:1) HCl solution at 0° C. The solutionwas kept at room temperature for 24 h. The deprotected azepinecrystallized, and the reaction mixture was cooled to 0° C. beforefiltration. The white crystals were washed with dry ether then dissolvedin pure water. The water solution was extracted twice with ether beforebeing yand lyophilised. 66.4 g (95% yield) 4-Hydroxy-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1)was obtained as a white powder

MS: 371.4 (M+H)⁺

IR (KBr): 3212, 1702, 1608, 1543, 1508, 1441 cm⁻¹

In analogy there were obtained

2) 4-Hydroxy-benzoic acid(3R,4R)-3-[4-(4-hydroxy-benzoyloxy)-benzoylamino]-azepan-4-yl esterhydrochloride (1:1) from (3R,4R)4-[4-(Tetrahydro-pyran-2-yloxy)-benzoyloxy]-3-{4-(4-(tetrahydro-pyran-2-yloxy)-benzoyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester

MS: 491 (M+H)⁺

IR: 3414, 3239, 3118, 2803, 1706, 1646, 1607, 1562, 1513 cm⁻¹

3) 4-(4-Nitro-benzoyloxy)-benzoic acid(3R,4R)-3-[4-hydroxy-benzoylamino)-azepan-4-yl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-[4-(4-nitro-benzoyloxy)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester

MS: 520.7 (M+H)⁺

IR (KBr): 3423, 2955, 2855, 2802, 1745, 1718, 1637, 1606, 1528, 1504cm⁻¹

EXAMPLE IV

The starting compounds used in Examples I-III were prepared bydesilylation (A.) and/or hydrogenolytic debenzylation (B.) ofcorresponding precursors as follows:

A. 754 mg of(3R,4R)-4-(Biphenyl-4-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester were dissolved in 10 ml tetrahydrofuran and 147 mgof tetrabutylammoniumfluoride trihydrate were added at 0° C. and thereaction mixture was stirred for two hours at room temperature. 2.5 mlof a saturated solution of sodium chloride and 2.5 ml of an aqueous 1molar solution of citric acid were added. The organic layer wasconcentrated under vacuo diluted with ethyl acetate then washed with 5ml of a saturated solution of sodium chloride dried over magnesiumsulfate and evaporated. The crude compound was purified on silica gel(dichloromethane:ethylacetate 1:1) to yield 551 mg (89% yield) of(3R,4R)-4-(Biphenyl-4-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester.

MS: 531 (M+H)⁺

IR: 3352, 2967, 2933, 1713, 1666, 1609, 1540, 1505, 1417 cm⁻¹

B. 80 mg(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester was dissolved in tetrahydrofuran. 10 mg 5%palladium on charcoal was added and the mixture hydrogenated atatmospheric pressure and room temperature for 2 hours. The catalyst wasfiltered on, the pad washed with tetrahydrofuran and the filtrateevaporated under reduced pressure. The residue was purified bychromatography on silica gel (10 g, AcOEt/Hexane 1:1 eluent) to afford56 mg (80% yield)(3R,4R)-3-[4-(4-Fluoro-benzoyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester as a colorless foam

MS: 593.6 (M+H)⁺

IR: 3400, 1742, 1707, 1664, 1606, 1548, cm⁻¹

In analogy there were prepared

1)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

2)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(naphthalen-1-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(naphthalene-1-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

3)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(2-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(2-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester

4)(3R,4R)-4-(4-tert-Butoxycarbonylamino-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(4-tert-Butoxycarbonylamino-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

5)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(3-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester

6)(3R,4R)-4-(Biphenyl-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(Biphenyl-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

7) 3-Methoxy-phthalic acid(3R,4R)-1-[1-tert-butoxycarbonyl-3-(4-hydroxy-benzoylamino)-azepan-4-yl]ester2-methyl ester from (3R,4R)-3-Methoxy-phthalic acid(3R,4R)-1-{1-tert-butoxycarbonyl-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepan-4-yl}ester2-methyl ester

8)(3R,4R)-4-(3,5-Dimethoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3,5-dimethoxy-naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

9)(3R,4R)-4-(3,7-Dimethoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3,7-dimethoxy-naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

10)4-(2,5-Dichloro-3-nitro-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(2,5-dichloro-3-nitro-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester

11)(E)-(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-[3-(4-hydroxy-phenyl)-acryloyloxy]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-(3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-phenyl}-acryloyloxy)-azepane-1-carboxylicacid tert-butyl ester

12)(3R,4R)-4-(3',4'-Dimethoxy-biphenyl-4-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(E)-(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3',4'-dimethoxy-biphenyl-4-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester

13)(3R,4R)-4-(3,4-Dihydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(3,4-Bis-benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

14)(3R,4R)-4-(2,3-Dihydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2,3-Bis-benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

15)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(7-hydroxy-3-methoxy-naphthalene-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(7-Benzyloxy-3-methoxy-naphthalen-2-yl-carbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

16)(3R,4R)-4-(2,4-Dihydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2,4-Bis-benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

17)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(5-hydroxy-3-methoxy-naphthalene-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(5-Benzyloxy-3-methoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

18)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(3-hydroxy-5-methoxy-naphthalene-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(3-Benzyloxy-5-methoxy-naphthalen-2-yl-carbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

19)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(3-hydroxy-7-methoxy-naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(3-Benzyloxy-7-methoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

20)(3R,4R)-4-(5-Fluoro-2-hydroxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2-Benzyloxy-5-fluoro-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

21)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(4-hydroxy-3,5-dimethoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester(3R,4R)-4-(4-Benzyloxy-3,5-dimethoxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

22)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-[4-(2-hydroxy-benzoylamino)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester(3R,4R)-4-[4-(2-Benzyloxy-benzoylamino)-benzoyloxy]-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

23)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-{4-[(2-hydroxy-benzoyl)-methyl-amino]-benzoyloxy}-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-{4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoyloxy}-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

24)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(2-hydroxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2-Benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

25)(3R,4R)-3-(4-Hydroxy-benzoylamino)-4-(naphthalene-1-carbonyloxy)-[4-(2-hydroxy-phenoxysulfonyl)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-[4-(2-Benzyloxy-phenoxysulfonyl)-benzoyloxy]-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester

26)(3R,4R)-4-{4-[(2,6-Dihydroxy-benzoyl)-methyl-amino]-benzoyloxy}-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-{4-[(2,6-Bis-benzyloxy-benzoyl)-methyl-amino]-benzoyloxy}-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

EXAMPLE V

The starting compounds used in Example IV were prepared by either

a) desilylation of a corresponding precursor (see d) below), or

b) esterification of(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester with 2,6-Bis-benzyloxy-benzoic acid or4-Fluoro-benzoic acid, or

c) esterification of(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester or(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester with acids activated by sulfonyl chloride,carbodiimide and the like or by esterification of a mixture of(3R,4R)-4-hydroxy-3-[4-[(R)-and-[(S)-tetrahydro-pyran-2-yloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester and(3R,4R)-4-Hydroxy-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylic acidtert-butyl ester with (RS)-4-(Tetrahydro-pyran-2-yloxy)-benzoic acid orby esterification of(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-esterwith p-nitrobenzoic acid.

In this manner, the following compounds were prepared:

1)(3R,4R)-4-(3,4-Bis-benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(3,4-Bis-benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

2)(3R,4R)-4-(2,3-Bis-benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2,3-Bis-benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

3)(3R,4R)-4-(7-Benzyloxy-3-methoxy-naphthalen-2-naphthalen-2-naphthaleneyl-2-carbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(7-Benzyloxy-3-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

4)(3R,4R)-4-(2,4-Bis-benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from3R,4R)-4-(2,4-Bis-benzyloxy-benzoyloxy)-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester

5)(3R,4R)-4-(5-Benzyloxy-3-methoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(5-Benzyloxy-3-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

6)(3R,4R)-4-(3-Benzyloxy-5-methoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(3-Benzyloxy-5-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

7)(3R,4R)-4-(3-Benzyloxy-7-methoxy-naphthalen-2-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(3-Benzyloxy-7-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

8)(3R,4R)-4-(2-Benzyloxy-5-fluoro-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2-Benzyloxy-5-fluoro-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

9)(3R,4R)-4-(4-Benzyloxy-3,5-dimethoxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(4-Benzyloxy-3,5-dimethoxy-benzoyloxy)-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester

10)(3R,4R)-4-[4-(2-Benzyloxy-benzoylamino)-benzoyloxy]-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-[4-(2-Benzyloxy-benzoylamino)-benzoyloxy]-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

11)(3R,4R)-4-[4-(2,6-Bis-benzyloxy-benzoylamino)-benzoyloxy]-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-[4-(2,6-Bis-benzyloxy-benzoylamino)-benzoyloxy]3-[4-tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

12)(3R,4R)-4-{4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoyloxy}-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-{4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoyloxy}-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

13)(3R,4R)-4-(2-Benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(2-Benzyloxy-benzoyloxy)-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester

14)(3R,4R)-4-[4-(2-Benzyloxy-phenoxysulfonyl)-benzoyloxy]-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-[4-(2-Benzyloxy-phenoxysulfonyl)-benzoyloxy]-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester

15)(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

16)(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-(4-(2,6-bis-benzyloxy-benzoyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester and 2,6-Bis-benzyloxy-benzoic acid

17)(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester and 4-Fluoro-benzoic acid

18)(3R,4R)-4-(Biphenyl-4-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and Biphenyl-4-carboxylic acid

19)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and Naphthalene-2-carboxylic acid

20)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(naphthalene-1-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and Naphthalene-1-carboxylic acid

21)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(2-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 2-Phenoxy-benzoic acid

22)(3R,4R)-4-(4-tert-Butoxycarbonylamino-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-tert-Butoxycarbonylamino-benzoic acid

23)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3-phenoxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-Phenoxy-benzoic acid

24)(3R,4R)-4-(Biphenyl-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and Biphenyl-2-carboxylic acid

25) (3R,4R)-3-Methoxy-phthalic acid(3R,4R)-1-{1-tert-butoxycarbonyl-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepan-4-yl}ester2-methyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3-Methoxy-phthalic acid 2-methyl ester

26)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3,5-dimethoxy-naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3,5-Dimethoxy-naphthalene-2-carboxylic acid

27)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3,7-dimethoxy-naphthalen-2-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3,7-Dimethoxy-naphthalene-2-carboxylic acid

28)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(2,5-dichloro-3-nitro-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 2,5-Dichloro-3-nitro-benzoic acid

29)(3R,4R)-3-{4-(Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-(3-{4-(dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-phenyl}-acryloyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and(E)-(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-phenyl}-acrylicacid

30)(E)-(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(3',4'-dimethoxy-biphenyl-4-ylcarbonyloxy)-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3',4'-Dimethoxy-biphenyl-4-carboxylic acid

31)(3R,4R)-4-(3,4-Bis-benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3,4-Bis-benzyloxy-benzoic acid

32)(3R,4R)-4-(2,3-Bis-benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 2,3-Bis-benzyloxy-benzoic acid

33)(3R,4R)-4-(7-Benzyloxy-3-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 7-Benzyloxy-3-methoxy-naphthalene-2-carboxylicacid

34)(3R,4R)-4-(2,4-Bis-benzyloxy-benzoyloxy)-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 2,4-Bis-benzyloxy-benzoic acid

35)(3R,4R)-4-(5-Benzyloxy-3-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 5-Benzyloxy-3-methoxy-naphthalene-2-carboxylicacid

36)(3R,4R)-4-(3-Benzyloxy-5-methoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3-Benzyloxy-5-methoxy-naphthalene-2-carboxylicacid

37)(3R,4R)-4-(3-Benzyloxy-7-metahoxy-naphthalen-2-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 3-Benzyloxy-7-methoxy-naphthalene-2-carboxylicacid

38)(3R,4R)-4-(2-Benzyloxy-5-fluoro-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from (3R,4R)-3-[4-(tertButyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 2-Benzyloxy-5-fluoro-benzoic acid

39)(3R,4R)-4-(4-Benzyloxy-3,5-dimethoxy-benzoyloxy)-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-Benzyloxy-3,5-dimethoxy-benzoic acid

40)(3R,4R)-4-[4-(2-Benzyloxy-benzoylamino)-benzoyloxy]-3-[4-tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-(2-Benzyloxy-benzoylamino)-benzoic acid

41)(3R,4R)-4-[4-(2,6-Bis-benzyloxy-benzoylamino)-benzoyloxy]-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-(2,6-Bis-benzyloxy-benzoylamino)-benzoicacid

42)(3R,4R)-4-{4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoyloxy}-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoicacid

43)(3R,4R)-4-{4-[(2,6-Bis-benzyloxy-benzoyl)-methyl-amino]-benzoyloxy}-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and4-[(2,6-Bis-benzyloxy-benzoyl)-methyl-amino]-benzoic acid

44)(3R,4R)-4-(2-Benzyloxy-benzoyloxy)-3-{4-(dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 2-Benzyloxy-benzoic acid

45)(3R,4R)-4-[4-(2-Benzyloxy-phenoxysulfonyl)-benzoyloxy]-3-{4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoylamino}-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-(2-Benzyloxy-phenoxysulfonyl)-benzoic acid

46)(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-hydroxy-azepane-1-carboxylicacid tert-butyl ester and 4-Benzyloxy-benzoic acid

47)(3R,4R)-3-[4-(Tetrahydro-pyran-2-yloxy)-benzoylamino]-4-[4-(tetrahydro-pyran-2-yloxy)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester (mixture of 4 diast.) from mixture of(3R,4R)-4-hydroxy-3-[4-[(R)-and-[(S)-tetrahydro-pyran-2-yloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester and (RS)-4-(Tetrahydro-pyran-2-yloxy)-benzoic acid

48) (3R,4R)4-[4-(Tetrahydro-pyran-2-yloxy)-benzoyloxy]-3-{4-[4-(tetrahydro-pyran-2-yloxy)-benzoyloxy]-benzoylamino}-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-4-Hydroxy-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylic acidtert-butyl ester and (RS)-4-(Tetrahydro-pyran-2-yloxy)-benzoic acid

49)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-[4-(4-nitro-benzoyloxy)-benzoyloxy]-azepane-1-carboxylicacid tert-butyl ester from(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester and 4-Nitro-benzoic acid

50) (3R,4R)-3,4-Dihydroxy-azepane-1-carboxylic acid tert-butyl ester wasprepared by hydrogenation of(3R,4R)-4-Benzyloxy-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester

EXAMPLE VI

Examples of esters and their preparation used in Example V d) are

1) mixture of (3R,4R)-4-hydroxy-3-[4-[(R)-and-[(S)-tetrahydro-pyran-2-yloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester by hydrogenation of mixture of(3R,4R)-4-benzyloxy-3-[4-[(R)-and-[(S)-tetrahydro-pyran-2-yloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester which is prepared by esterification of(3R,4R)-3-Amino-4-benzyloxy-azepane-1-carboxylic acid tert-butyl esterand (RS)-4-(Tetrahydro-pyran-2-yloxy)-benzoic acid

2) (3R,4R)-4-Hydroxy-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester by hydrogenation of(3R,4R)-4-Benzyloxy-3-(4-benzyloxy-benzoylamino)-azepane-1-carboxylicacid tert-butyl ester which is prepared by esterification of(3R,4R)-3-Amino-4-benzyloxy-azepane-1-carboxylic acid tert-butyl esterand 4-benzyloxy-benzoic acid

3)(3R,4R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylicacid tert-butyl ester by hydrogenation of(3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylicacid tert-butyl ester

EXAMPLE VII

Preparation of tert-Butyl(3R,4R)-3-amino-4-benzyloxy-azepane-1-carboxylate:

Ethyl 2,3-dideoxy-alpha-D-erythrohexopyranoside was converted withp-toluenesulphonyl chloride into ethyl6O-(p-tolylsulphonyl)-2,3-dideoxy-alpha-D-erythrohexopyranoside. Byreaction with sodium azide, there was obtained therefrom ethyl6-azido-2,3,6-trideoxy-a-D-erythrohexopyranoside and therefrom with4-nitrobenzoic acid under Mitsunobu conditions there was obtained ethyl6-azido-2,3,6-trideoxy-4-O(4-nitrobenzoyl)-alpha-D-threohexopyranoside.Basic hydrolysis of the latter compound yielded ethyl6-azido-2,3,6-trideoxy-a-D-galactopyranoside which by benzylation andsubsequent acidic hydrolysis was converted into6-azido-5O-benzyl-2,3,6-trideoxy-D-galactopyranose. Catalytichydrogenation (PtO/room temperature) and subsequent reaction withbis-tert-butyl carbonate yielded tert butyl(3S,4R)-4(benzyloxy)-hexahydro-3-hydroxy-1H-azepine-1-carboxylate.Acylation under Mitsunobu conditions to tert butyl(3S,4R)-4-(benzyloxy)-hexahydro-3-O-(4-nitrobenzoyl)-1H-azepine-1-carboxylate,basic hydrolysis and reaction with hydrazoic acid under Mitsunobuconditions yielded tert-butyl(3R,4R)-3-azido-4-(benzyloxy)-hexahydro-1H-azepine-1-carboxylate, fromwhich tert-Butyl (3R,4R)-3-amino-4-benzyloxy-azepane-1-carboxylate wasobtained by hydrogenation (Pd/C).

EXAMPLE VIII

Other starting materials used in the preceding Examples were obtained asfollows:

1) 7-Benzyloxy-3-methoxy-naphthalene-2-carboxylic acid from3,7-Dihydroxy-naphthalene-2-carboxylic acid via7-Benzyloxy-3-hydroxy-naphthalene-2-carboxylic acid methyl ester and7-Benzyloxy-3-methoxy-naphthalene-2-carboxylic acid methyl ester;

2) 5-Benzyloxy-3-methoxy-naphthalene-2-carboxylic acid from3,5-Dihydroxy-naphthalene-2-carboxylic acid via5-Benzyloxy-3-hydroxy-naphthalene-2-carboxylic acid methyl ester; and5-Benzyloxy-3-methoxy-naphthalene-2-carboxylic acid methyl ester;

3) 3-Benzyloxy-5-methoxy-naphthalene-2-carboxylic acid from3-Hydroxy-5-methoxy-naphthalene-2-carboxylic acid methyl ester via3-Benzyloxy-5-methoxy-naphthalene-2-carboxylic acid methyl ester;

4) 3-Benzyloxy-7-methoxy-naphthalene-2-carboxylic acid from3-Hydroxy-7-methoxy-naphthalene-2-carboxylic acid methyl ester via3-Benzyloxy-7-methoxy-naphthalene-2-carboxylic acid methyl ester;

5) 4-(2,6-Bis-benzyloxy-benzoylamino)-benzoic acid from2,6-Bis-benzyloxy-benzoic acid and 4-Amino-benzoic acid methyl ester via4-(2,6-Bis-benzyloxy-benzoylamino)-benzoic acid methyl ester;

6) 4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoic acid from4-(2-Benzyloxy-benzoylamino)-benzoic acid methyl ester via4-[(2-Benzyloxy-benzoyl)-methyl-amino]-benzoic acid methyl ester;

7) 4-[(2,6-Bis-benzyloxy-benzoyl)-methyl-amino]-benzoic acid from4-(2,6-Bis-benzyloxy-benzoylamino)-benzoic acid methyl ester via4-[(2,6-Bis-benzyloxy-benzoyl)-methyl-amino]-benzoic acid methyl ester;

8)(E)-(3R,4R)-3-{4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-phenyl}-acrylicacid from (E)-3-(4-Hydroxy-phenyl)-acrylic acid;

9) 4-(2-Benzyloxy-phenoxysulfonyl)-benzoic acid from 2-Benzyloxy-phenoland 4-Chlorosulfonyl-benzoic acid.

Examples A-F illustrate the manufacture of pharmaceutical preparations.

EXAMPLE A

Hard gelatin capsules can be produced as follows:

    ______________________________________                                        Ingredients                mg/capsule                                         ______________________________________                                        1. Spray-dried powder containing 75% compound I                                                          20                                                   2. Sodium dioctylsulphocuccinate 0.2                                          3. Sodium carboxymethylcellulose 4.8                                          4. Microcrystalline cellulose 86.0                                            5. Talc 8.0                                                                   6. Magnesium stearate 1.0                                                   Total                      120.0                                              ______________________________________                                    

The spray-dried powder, which is based on the active ingredient, gelatinand microcrystalline cellulose and which has an average activeingredient particle size of <1μ (measured by autocorrelationspectroscopy), is moistened with an aqueous solution of sodiumcarboxymethylcellulose and sodium dioctylsulphocuccinate and kneaded.The resulting mass is granulated dried and sieved. The granulateobtained is mixed with microcrystalline cellulose, talc and magnesiumstearate. The mixture is filled into size 0 capsules.

EXAMPLE B

Tablets can be produced as follows:

    ______________________________________                                        Ingredients            mg/tablet                                              ______________________________________                                        1. Compound I as a finely milled powder                                                               20                                                      2. Powd. lactose 100                                                          3. White corn starch  60                                                      4. Povidone K30  8                                                            5. White corn starch 112                                                      6. Talc  16                                                                   7. Magnesium stearate  4                                                    Total                  320                                                    ______________________________________                                    

The finely milled substance is mixed with lactose and the (3.) portionof the corn starch. The mixture is moistened with an aqueous solution ofPovidone K30 and kneaded, and the resulting mass is granulated, driedand sieved. The granulate is mixed with the remaining corn starch (5.),talc and magnesium stearate and pressed to tablets of suitable size.

EXAMPLE C

Soft gelatin capsules can be produced as follows:

    ______________________________________                                        Ingredients    mg/capsule                                                     ______________________________________                                        1. Compound I   5                                                               2. Triglyceride 450                                                         Total          455                                                            ______________________________________                                    

10 g of compound I are dissolved in 90 g of medium chain triglyceridewith stirring, inert gasification and protection from light. Thissolution is processed as a capsule fill mass to soft gelatin capsulescontaining 5 mg of active ingredient.

EXAMPLE D

A cream can be produced from the ingredients listed hereinafter in aknown manner:

    ______________________________________                                                            Wt. %                                                     ______________________________________                                        Compound of Formula I.                                                                              0.1-5                                                     Cetyl alcohol 5.25-8.85                                                       Arlacel 165 (glyceryl/PEG 100 stearate) 3.75-6.25                             Miglyol 818 (caprylic/capric/linoleic acid) 11.25-18.75                       Sorbitol solution 3.75-6.25                                                   EDTA Na.sub.2 0.075-0.125                                                     Carbopol 934P (carbomer 934P) 0.15-0.25                                       Butylated hydroxyanisole 0.0375-0.0625                                        Methylparaben 0.135-0.225                                                     Propylparaben 0.0375-0.0625                                                   NaOH (10% solution) 0.15-0.25                                                 Water q.s. 100.00                                                           ______________________________________                                    

The physical properties of the preparations can be altered by varyingthe ratio between the adjuvants.

EXAMPLE E

A gel can be produced from the ingredients listed hereinafter in a knownmanner:

    ______________________________________                                                              Wt. %                                                   ______________________________________                                        Compound of Formula I   0.1-5                                                   Pluronic L 101 (poloxamer 331) 10.00                                          Aerosil (silicion dioxide) 8.00                                               PCL liquid (fatty acid ester) 15.00                                           Cetiol V (decyl oleate) 20.00                                                 Neobee oil (medium chain length triglyceride) 15.00                           Euhanol G (octyldodecanol), q.s. 100.00                                     ______________________________________                                    

EXAMPLE F

A solution can be prepared from the following ingredients

    ______________________________________                                        Ingredients         mg                                                        ______________________________________                                        Compound of formula I                                                                              10                                                         Propylene glycol 100                                                          Ethanol 94% (VIV) 300                                                         Phosphoric acid ca. 85%  5                                                    1 N NaOH ad pH 3                                                              Demineralized water ad 1 ml                                                 ______________________________________                                    

What is claimed is:
 1. The compound which is4-Hydroxy-benzoic acid(3R,4R)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepan-4-yl ester. 2.The compound which is4-Hydroxy-benzoic acid(3R,4R)-3-[4-(2,6-dihydroxy-benzoyloxy)-benzoylamino]-azepan-4-yl ester.3. The compound which is4-Hydroxy-benzoic acid(3R,4R)-3-[4-(4-hydroxy-benzoyloxy)-benzoylamino]-azepan-4-yl ester. 4.The compound which is3-Methoxy-phthalic acid(3R,4R)-1-[3-(4-hydroxy-benzoylamino)-azepan-4-yl]ester 2-methyl ester.5. The compound which is2,5-Dichloro-3-nitro-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.
 6. The compoundwhich is3-(4-Hydroxy-phenyl)-acrylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.
 7. The compoundwhich is3',4'-Dimethoxy-biphenyl-4-carboxylic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.
 8. The compoundwhich is4-[(2-Hydroxy-benzoyl)-methyl-amino]-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.
 9. The compoundwhich is4-[(2,6-Dihydroxy-benzoyl)-methyl-amino]-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.
 10. The compoundwhich is4-(2-Hydroxy-phenoxysulfonyl)-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.
 11. The compoundwhich is4-(4-Nitro-benzoyloxy)-benzoic acid(3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester.